443 | A PHASE 1 STUDY OF PRT2527, A SELECTIVE CDK9 INHIBITOR, AS MONOTHERAPY AND IN COMBINATION WITH ZANUBRUTINIB IN RELAPSED/REFRACTORY LYMPHOID MALIGNANCIES: UPDATED ANALYSIS

Introduction: CDK9, a key transcription elongation regulator, is a potential target in transcriptionally addicted cancers dependent on oncogenic drivers with short half-lives. The BTK inhibitor zanubrutinib (zanu) upregulates BCL2-modifying factor, a proapoptotic molecule inhibited by BCL2, BCLXL, and BCLW. CDK9 and BTK inhibition may synergistically enhance apoptotic priming and shift dependency toward the CDK9 targets. Methods: Phase 1 study of PRT2527, a highly selective potent CDK9 inhibitor, as monotherapy (mono) and in combination (combo) with zanu in patients (pts) with select relapsed/refractory (R/R) hematologic malignancies (NCT05665530). Pts must be R/R to or ineligible for standard-of-care therapy. PRT2527 administered intravenously as a once-weekly infusion in escalating doses guided by BOIN based on dose-limiting toxicities (DLTs) in cycle 1; zanu administered orally. Results: As of January 31, 2025, 56 pts with lymphoma (20 DLBCL-NOS, 4 HGBL, 2 Richter syndrome, 20 TCL, 6 MCL, and 4 CLL/SLL) were enrolled and treated with PRT2527. Median age was 64 (range, 27–94) years, 59% were male, and median prior lines of therapy was 3 (range, 1–7). Thirty-five pts were treated with PRT2527 mono (9 mg/m2, n = 6; 15 mg/m2, n = 5; 18 mg/m2, n = 18; 24 mg/m2, n = 6) and 21 with PRT2527 + zanu combo (9 mg/m2, n = 6; 15 mg/m2, n = 7, 18 mg/m2, n = 8). Median duration of study treatment was 6 weeks (range, 1.0–39.0) for mono and 13 weeks (range, 4.4–45.0) for combo. Ten (18%) pts remained on study (mono, n = 3; combo, n = 7), and 46 (82%) discontinued treatment mainly due to progressive disease (66%) and adverse events (AEs; 9%). Most frequent (> 20%) any-grade treatment-emergent AEs (TEAEs) were neutropenia (46%), nausea (38%), and anemia (21%) in all pts. Most frequent grade ≥ 3 TEAEs were neutropenia (43%), anemia (11%), thrombocytopenia (9%), and febrile neutropenia, sepsis, and pneumonia (5% each). Twenty-five (45%) pts had a TEAE leading to PRT2527 dose hold: 14 (25%) due to neutropenia, with 13 resolved with growth factor, and 1 due to febrile neutropenia. One DLT of grade 3 tumor lysis syndrome (TLS) occurred in a pt with CTCL (mycosis fungoides) with 24 mg/m2 mono. Responses shown in Table. Whole blood expression of MCL1 and MYC showed target engagement at all doses. At 18 mg/m2 (n = 13), a median decrease of 74% in MCL1 and 88% in MYC mRNA was achieved at end of infusion. At 6 h, MCL1 and MYC levels remained suppressed with median inhibition of 20% and 34%, respectively. Conclusions: PRT2527 had an acceptable safety profile with activity observed in both mono and in combo with zanu, including CR in 2 pts relapsed after CAR-T and responses in CLL/SLL post BTK. Most common TEAE was neutropenia, manageable with growth factor support. One DLT (grade 3 TLS) was observed in mono (24 mg/m2) and no DLTs in combo. Data supports further evaluation of PRT2527 at 18 mg/m2 (recommended phase 2 dose) as mono in PTCL and in combo with zanu in aggressive B-cell lymphoma. Research funding declaration: Prelude Therapeutics Incorporated Keywords: non-Hodgkin; molecular targeted therapies; molecular targeted therapies Potential sources of conflict of interest: W. Jurczak Consultant or advisory role: Abbvie/Genentech, AstraZeneca, BeiGene, Janssen-Cillag, Lilly, and Takeda Other remuneration: Research Funding: Abbvie/Genentech, AstraZeneca, BeiGene, Janssen- Cillag, Lilly, Merck, MSD, Prelude Therapeutics, Roche, and Takeda C. Sarkozy Consultant or advisory role: Janssen, BeiGene, Roche, Bristol Myers Squibb, and MSD Honoraria: AstraZeneca, BeiGene, and AbbVie Educational grants: Roche, Gilead Other remuneration: Research Funding: Roche K. L. Lewis Consultant or advisory role: AstraZeneca, Roche, Merck/MSD, and AbbVie Honoraria: Janssen, Roche, AstraZeneca, and Gilead/Kite Other remuneration: Patents/Royalties: Loxo/Lilly, AstraZeneca; Advisory Board: AbbVie, Merck/MSD, and IQVIA; Trial Steering Committee: Loxo/Lilly G. Shouse Consultant or advisory role: BeiGene, Kite Pharma Honoraria: BeiGene, Kite Pharma Other remuneration: Speakers Bureau: BeiGene, Kite Pharma, and ADC Therapeutics E. A. Hawkes Consultant or advisory role: Roche, Merck Sharp & Dohme, AstraZeneca, Gilead, Antengene, Novartis, Regeneron, Janssen, Specialised Therapeutics, and Sobi Educational grants: AstraZeneca Other remuneration: Research Funding: Roche, AstraZeneca, Merck KGaA, Bristol Myers Squibb, TG Therapeutics and Merck; Speakers Bureau: Regeneron; Expert Testimony: Specialised Therapeutics W. S. Kim Other remuneration: Grant/Research Support: Sanofi, BeiGene, Boryong, Roche, Kyowa-Kirin, and Donga M. Tani Consultant or advisory role: Roche, Lilly, BeiGene, and AstraZeneca Honoraria: Sobi, AbbVie Educational grants: Janssen-Cilag F. Lemonnier Consultant or advisory role: Bristol Myers Squibb, Kiowa Educational grants: BeiGene, Kite, and AbbVie S. E. Assouline Consultant or advisory role: Roche, AstraZeneca, Novartis, Gilead, and BeiGene Honoraria: Roche, AstraZeneca, Norvatis, Gilead, AbbVie, and Beigene Other remuneration: Research Funding: Novartis; Speakers Bureau: Roche, Novartis F. Morschhauser Consultant or advisory role: Roche, Bristol Myers Squibb, and Gilead Honoraria: Takeda, Roche, and Chugai Other remuneration: Participation on a Data Safety Monitoring Board or Advisory Board: Gilead, Bristol Myers Squibb, and AbbVie B. D. Cheson Employment or leadership position: American Oncology Network Consultant or advisory role: AbbVie, AstraZeneca, Regeneron, Calyx, and Imaging Endpoints Honoraria: BeiGene, Lilly Other remuneration: Leadership: Symbio Pharmaceuticals; Research Funding: Lilly, BeiGene, Genentech, and Prelude; Speakers Bureau: Lilly C. S. Diefenbach Employment or leadership position: NYU Grossman School of Medicine/Perlmutter Cancer Center at NYU Langone Health Consultant or advisory role: Bristol Myers Squibb, Celgene, Genentech/Roche, Genmab, I MAB, Incyte, Merck, MorphoSys, Seattle Genetics Stock ownership: Gilead Sciences, OverT Therapeutics Other remuneration: Membership on a Board or Advisory Committee: AstraZeneca; Research Funding: Bristol Myers Squibb, FATE Therapeutics, Genentech/Roche, Incyte, MEI Pharma, Merck, Millenium, Seattle Genetics G. P. Gregory Consultant or advisory role: Roche/Genentech, Merck, Gilead Kite, Amgen, and Prelude Therapeutics Educational grants: Novartis Other remuneration: Research Funding: Merck, BeiGene, AbbVie; Speakers Bureau: Roche/Genentech, Gilead Kite T. Munir Consultant or advisory role: Abbvie, Lilly, AstraZeneca, Johnson and Johnson, and Novartis Honoraria: Johnson and Johnson, AstraZeneca, BeiGene, Lilly, and AbbVie Other remuneration: Research Funding: Johnson and Johsnon, AbbVie; Speakers Bureau: Johnson and Johnson, AstraZeneca, BeiGene, Lilliy, Sobi, and Novartis P. Langerbeins Consultant or advisory role: Janssen, AbbVie, AstraZeneca, and BeiGene Honoraria: Janssen, AbbVie, AstraZeneca, and BeiGene Educational grants: Janssen, AbbVie, AstraZeneca, and BeiGene Other remuneration: Research Funding: Janssen-Cilag C. S. Tam Honoraria: Janssen, AbbVie, BeiGene, and AstraZeneca Other remuneration: Research Funding: AbbVie, Janssen G. Musuraca Consultant or advisory role: Janssen, Roche, AbbVie, Genmab, Incyte, Takeda, BeiGene, AstraZeneca, SOBI, and Lilly Educational grants: Janssen, AbbVie, AstraZeneca Other remuneration: Speakers Bureau: Genmab, Incyte, Lilly, and AbbVie; Expert Testimony: Genmab, Incyte, Lilly, and AbbVie C. A. Portell Consultant or advisory role: AstraZeneca, BeiGene, Jansen, Merck, and Genentech Honoraria: Pfizer Other remuneration: Research Funding: AbbVie, Genentech, Prelude, Lilly, AstraZeneca, Pfizer, Acerta, and BeiGene A. Stathis Consultant or advisory role: Debiopharm, Janssen, AstraZeneca, Incyte, Eli Lilly, Novartis, Roche, and Loxo Oncology Educational grants: Incyte, AstraZeneca Other remuneration: Research Funding: Abbvie, ADC Therapeutics, Amgen, Astra Zeneca, Bayer, BMS, Cellestia, Debiopharm, Incyte, Loxo Oncology, Merck MSD, Novartis, Pfizer, Philogen, Prelude Therapeutics, and Roche J. Xavier Employment or leadership position: Prelude Therapeutics Consultant or advisory role: Sanofi, Pfizer, and Genentech Stock ownership: Prelude Therapeutics Other remuneration: Research Funding: Genentech, Sanofi; Patents, Royalities: Incanthera Ltd M. Osman Employment or leadership position: Prelude Therapeutics Stock ownership: Prelude Therapeutics, AstraZeneca S. K. Atwal Employment or leadership position: Prelude Therapeutics Stock ownership: Prelude Therapeutics, BeiGene J. Huang Employment or leadership position: Prelude Therapeutics, Protara Stock ownership: Prelude Therapeutics, BeiGene Other remuneration: Patents, Royalties: Prelude Therapeutics P. L. Zinzani Honoraria: Kyowa Kirin, Roche, AbbVie, BeiGene, Bristol Myers Squibb, Gilead, Novartis, Incyte, and Sobi Other remuneration: Speakers Bureau: Kyowa Kirin, Roche, AbbVie, BeiGene, Bristol Myers Squibb, Gilead, Novartis, Incyte, and Sobi

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